1solo.oa

The new england journal of medicine
Scott D. Solomon, M.D., John J.V. McMurray, M.D.,
Marc A. Pfeffer, M.D., Ph.D., Janet Wittes, Ph.D., Robert Fowler, M.S.,
Peter Finn, M.D., William F. Anderson, M.D., M.P.H., Ann Zauber, Ph.D.,
Ernest Hawk, M.D., M.P.H., and Monica Bertagnolli, M.D.,
for the Adenoma Prevention with Celecoxib (APC) Study Investigators*
b a c k g r o u n d
Selective cyclooxygenase-2 (COX-2) inhibitors have come under scrutiny because of re- From the Cardiovascular Division, Depart-
ports suggesting an increased cardiovascular risk associated with their use. Experimen- and Surgery (M.B.), Brigham and Women’s
tal research suggesting that these drugs may contribute to a prothrombotic state pro- Hospital, Harvard Medical School, Boston;vides support for this concern.
Western Infirmary, University of Glasgow,Glasgow, Scotland (J.J.V.M.); Statistics Col-laborative, Washington, D.C. (J.W., R.F.);
We reviewed all potentially serious cardiovascular events among 2035 patients with a (W.F.A., E.H.); and Memorial Sloan-Ketter-
ing Cancer Center, New York (A.Z.). Address
history of colorectal neoplasia who were enrolled in a trial comparing two doses of reprint requests to Dr. Solomon at the Car-
celecoxib (200 mg or 400 mg twice daily) with placebo for the prevention of colorectal diovascular Division, Brigham and Wom-adenomas. All deaths were categorized as cardiovascular or noncardiovascular, and en’s Hospital, 75 Francis St., Boston, MA
02115, or at [email protected]
nonfatal cardiovascular events were categorized in a blinded fashion according to a edu.
*Participants in the APC study are listed
For all patients except those who died, 2.8 to 3.1 years of follow-up data were available. N Engl J Med 2005;352.A composite cardiovascular end point of death from cardiovascular causes, myocardial Copyright 2005 Massachusetts Medical Society.infarction, stroke, or heart failure was reached in 7 of 679 patients in the placebo group(1.0 percent), as compared with 16 of 685 patients receiving 200 mg of celecoxib twicedaily (2.3 percent; hazard ratio, 2.3; 95 percent confidence interval, 0.9 to 5.5) and with23 of 671 patients receiving 400 mg of celecoxib twice daily (3.4 percent; hazard ratio,3.4; 95 percent confidence interval, 1.4 to 7.8). Similar trends were observed for othercomposite end points. On the basis of these observations, the data and safety monitor-ing board recommended early discontinuation of the study drug.
c o n c l u s i o n s
Celecoxib use was associated with a dose-related increase in the composite end pointof death from cardiovascular causes, myocardial infarction, stroke, or heart failure. Inlight of recent reports of cardiovascular harm associated with treatment with otheragents in this class, these data provide further evidence that the use of COX-2 inhibitorsmay increase the risk of serious cardiovascular events.
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The new england journal of medicine
enomatous polyps in the colon and rectum one year
of gastrointestinal side effects with the use and three years after endoscopic polypectomy. The
t of selective cyclooxygenase-2 (COX-2) in- trial was led by the Strang Cancer Prevention Cen-
hibitors than with the use of nonselective nonste- ter (New York) and cosponsored by the Nationalroidal antiinflammatory drugs (NSAIDs) or aspirin Cancer Institute and Pfizer. Ninety-one sites par-has led to a marked increase in prescriptions for ticipated (72 in the United States, 1 in the UnitedCOX-2 inhibitors, despite the fact that they offer Kingdom, 8 in Australia, and 10 in Canada). Partici-similar degrees of pain relief.1-3 In addition, the pants ranged from 32 to 88 years of age and wereidentification of COX-2 as a promoter of intestinal considered to have a clinically significant risk oftumorigenesis suggested that inhibiting this en- colorectal adenoma on the basis of a history of ei-zyme could prevent the formation of premalignant ther multiple adenomas or a single adenoma thatcolorectal adenomas.4-8 Recently, however, this was at least 0.5 cm in diameter. All known adeno-class of drugs has come under scrutiny because of mas were removed colonoscopically before drugclinical reports that they were associated with an treatment began.increased risk of serious cardiovascular harm.9-11
A detailed medical history, including baseline as-
The mechanism of this effect is suggested in part sessment of cardiovascular disease status and riskby evidence that selective inhibition of COX-2 can factors for cardiovascular disease, was obtained forblock the production of prostacyclin without af- each patient. The protocol was reviewed and ap-fecting the synthesis of thromboxane A ,10 thereby proved by the appropriate institutional review
potentially creating a prothrombotic state.
boards, and all patients provided written informed
The observation of an increased incidence of consent before enrollment. Patients were randomly
death from cardiovascular causes, myocardial in- assigned to treatment with the use of a computer-farction, or stroke among patients receiving rofe- generated randomization schedule. At the time ofcoxib in the Adenomatous Polyp Prevention on data review, 2035 patients had undergone random-Vioxx (APPROVe) trial and the associated voluntary ization in a double-blind manner at a 1:1:1 ratio,withdrawal of this drug from the market prompted after stratification according to the use or nonuse ofthe data and safety monitoring board and steering aspirin for cardiovascular prophylaxis and the en-committee of a similar ongoing trial of celecoxib to rolling center. Enrollment began in November 1999request a focused reassessment of data on cardio- and concluded in March 2002. Compliance was as-vascular safety by an independent committee, with sessed by means of both pill counts and standardthe results presented at their scheduled meeting on monitoring of medical records every 6 to 12 weeks.December 10, 2004. The study was a prospective,randomized, double-blind, multicenter trial assess- review of cardiovascular safetying the efficacy of celecoxib for the prevention of The cardiovascular safety committee developed end-adenomatous polyps in patients who had under- point definitions as guidelines for adjudication. Thegone endoscopic polypectomy. Because neither committee classified and adjudicated the end pointsprior clinical trials nor observational studies had by defining a hierarchy of composite end pointsreported a clearly increased risk of cardiovascular (based on clinical importance and the prior findingsevents with celecoxib use,2,5,12-16 this longer-term, with rofecoxib). These guidelines were designedplacebo-controlled trial provided an important op- specifically to assess cardiovascular safety (listedportunity to evaluate the potential association. This in the Supplementary Appendix, available with thereport describes the findings of the independent full text of this article at www.nejm.org). An initialcardiovascular safety committee.
review identified all deaths and potential nonfatalcardiovascular adverse events. Two experienced in-dependent assessors reviewed these events using
medical records and narratives supplied by site in-
p a t i e n t s
vestigators. Myocardial infarction was defined on
The Adenoma Prevention with Celecoxib (APC) the basis of either a clinical presentation character-study compared the efficacy and safety of 200 mg of ized by typical symptoms, signs, or electrocardio-celecoxib twice daily, 400 mg of celecoxib twice graphic changes associated with an elevation indaily, and placebo in reducing the occurrence of ad- the level of a cardiac marker or angiographic evi-
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c e l e c o x i b a n d c a r d i o v a s c u l a r r i s k
dence of coronary thrombosis. Stroke was defined available at the time of the original analysis. Thisas a persistent focal neurologic event whose onset analysis contains data on three additional cardio-was sudden and was not due to trauma or a tumor. vascular events that were not included in the origi-Other cardiovascular events were categorized ac- nal report.cording to a preplanned schema. When this initialdocumentation was insufficient for adjudication,
additional information was obtained from the in-vestigative sites.
At the time of the analysis, 77 percent of the 2035
The entire cardiovascular safety committee was patients had completed the study, and all of the re-
unaware of the patients’ treatment assignments maining surviving patients had completed at leastthroughout the review process. For the purposes of 2.8 years of follow-up (range, 2.8 to 3.1). The base-this analysis, we evaluated a hierarchy of compos- line characteristics were similar among the threeite end points, including death from cardiovascular groups (Table 1). The incidence of the prespecifiedcauses, myocardial infarction, stroke, heart failure, composite cardiovascular end points, analyzed ac-unstable angina, and the need for a cardiovascular cording to the time to the first event, and the asso-procedure.
ciated hazard ratios are shown in Table 2. As com-pared with the placebo group, the group given 200
s t a t i s t i c a l a n a l y s i s
mg of celecoxib twice daily had a hazard ratio for
Randomization codes were provided to Statistics death from cardiovascular causes, myocardial in-Collaborative (Washington, D.C.). All analyses were farction, stroke, or heart failure of 2.3 (95 percentperformed according to the intention-to-treat prin- confidence interval, 0.9 to 5.5), and the group re-ciple, with data on each patient analyzed according ceiving 400 mg of celecoxib twice daily had a hazardto the original randomized treatment assignment. ratio of 3.4 (95 percent confidence interval, 1.4 toLog-rank tests were used to compare the time to a 7.8). The results for the individual components ofcardiovascular event in the three groups for each the composite end point are shown in Table 3.composite end point of interest. Cox models, with
There were six deaths in the placebo group, six in
the treatment group as the only covariate, were the group given 200 mg of celecoxib twice daily, andused to estimate hazard ratios for the two celecoxib nine in the group given 400 mg twice daily, and one,groups as compared with the placebo group. Al- three, and six of the deaths, respectively, were duethough the randomization was stratified according to cardiovascular causes. The Kaplan–Meier curvesto the baseline use or nonuse of aspirin and the cen- for the combined end point of death from cardio-ter, the Cox models did not include these stratifying vascular causes, myocardial infarction, stroke, orvariables. Censoring was defined by assuming that heart failure in the three groups are shown in Fig-a patient was followed for 37 months, until death, ure 1. The annualized incidence of death from car-or until January 6, 2005 (the date defined for this diovascular causes, stroke, myocardial infarction, oranalysis as the common close-out date) — which- heart failure was 3.4 events per 1000 patient-yearsever came first. At the time of this review, we had in the placebo group, 7.8 events per 1000 patient-follow-up information for more than 97 percent of years in the group given 200 mg of celecoxib twicethe patient-years at risk. Incidence rates were cal- daily, and 11.4 events per 1000 patient-years in theculated for individual and composite cardiovascu- group given 400 mg twice daily.lar events by dividing the number of patients with
In addition to the increased risk of the prespec-
events by the number of patient-years at risk.
ified composite end point of cardiovascular events,
Important subgroups based on baseline charac- the point estimate of the number of venous throm-
teristics were prespecified. To examine whether the boembolic events was also increased (though noteffect of celecoxib varied between subgroups, we significantly) among patients receiving celecoxib:constructed Cox models with terms for treatment, four in the group given 400 mg of celecoxib twicesubgroup, and the interaction between subgroup daily and three in the group given 200 mg twice dai-and treatment and evaluated the interaction terms ly, as compared with one in the placebo group (haz-for statistical significance.
ard ratio for the two celecoxib groups combined,
Recommendations to the study’s data and safety 3.5; 95 percent confidence interval, 0.4 to 28.5).
monitoring board were made on the basis of data There was no apparent increase in the risk of un-
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The new england journal of medicine
Table 1. Baseline Characteristics of the Patients.* Celecoxib, 200 mgCelecoxib, 400 mg CharacteristicTwice Daily (N=685)Twice Daily (N=671)
History of cardiovascular events — no. (%)
* Plus–minus values are means ±SD. There were no significant differences among the groups.† Data were missing for one patient in the placebo group.
stable angina, arrhythmia, or the need for a cardio- treatment with 200 or 400 mg of celecoxib to pre-vascular procedure. The hazard ratios associated vent colorectal adenomas led to a dose-related in-with celecoxib use decreased when a broader class crease in the risk of serious cardiovascular events,of cardiovascular events, including unstable angi- including death from cardiovascular causes, myo-na and the need for a cardiovascular procedure, cardial infarction, stroke, and heart failure. Thesewas added to the composite end point. The hazard results were consistent among the individual com-ratio associated with celecoxib was not significant- ponents of the composite end point. Because thely affected by any of the baseline characteristics ex- use of other selective COX-2 inhibitors, includingamined, including aspirin use at baseline (Table 4). rofecoxib, valdecoxib, and parecoxib, has also been
On December 16, 2004, on the basis of these associated with an increased rate of cardiovascular
findings, the advice of the cardiovascular safety events,17,18 our results heighten concern that thiscommittee, and previous findings with drugs in the class of drug may be associated with increased car-same class, the data and safety monitoring board diovascular risk. The cardiovascular safety commit-concluded that continued exposure to celecoxib tee also completed a preliminary review of cardio-placed patients at increased risk for serious cardio- vascular safety in another study, the Prevention ofvascular events. On the basis of this recommenda- Spontaneous Adenomatous Polyps (PreSAP) trial,tion, the steering committee stopped the use of which randomly assigned patients with a history ofstudy medication among the patients remaining in colorectal adenomas to receive either 400 mg of cele-the trial. The trial remained blinded, and follow-up coxib once a day or placebo. The preliminary analy-for the end point of adenoma continued. Three sis did not show an increase in risk at this dose.events that were documented after the study was
The reason for the apparent increase in cardio-
stopped are included in the present analysis; their vascular risk associated with the use of COX-2 in-inclusion does not alter the overall conclusions of hibitors is uncertain. One prominent hypothesisthe report issued on December 16, 2004.
involves the effects of COX-2 inhibitors on two keyprostanoids, prostacyclin and thromboxane A ,
which have a crucial role in vascular homeosta-
sis.9,19,20 These prostanoids are generated by the
In a large, randomized, placebo-controlled, double- action of the cyclooxygenase-1 (COX-1) and COX-2blind, multicenter trial, we found that twice-daily isoenzymes on arachidonic acid.21 Thromboxane
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c e l e c o x i b a n d c a r d i o v a s c u l a r r i s k
elecoxib Celecoxib,Twice Daily elecoxib,hazard ratio (95% confidence interval)Twice Daily elecoxib elecoxib, Twice Daily elecoxib, Twice Daily elecoxib Groups Relative to the Placebo Group.elecoxib elecoxib, Twice Daily omposite End Points in the Celecoxib, Twice Daily Incidence of and Hazard Ratios for the CEnd Point*
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The new england journal of medicine
Table 3. Incidence of Individual Cardiovascular and Fatal Events.Celecoxib, 200 mg Celecoxib, 400 mg Both Celecoxib End PointTwice Daily (N=685)Twice Daily (N=671)Groups (N=1356)
Death from noncardiovascular causes 5 (0.7)
A , which promotes platelet aggregation, vasocon- however, were generally short-term studies designed
striction, and smooth-muscle proliferation, is syn- to assess the use of this class of drug for pain reliefthesized primarily in platelets, which express only and to evaluate associated adverse gastrointestinalCOX-1. Conversely, prostacyclin, which has antiag- events. They included a relatively small proportiongregative, antiproliferative, and vasodilatory actions, of patients at high risk for cardiovascular events oris the main prostanoid product of endothelial cells, excluded such patients, despite the fact that manysynthesized as a result of the action of COX-2.22
patients who are taking these drugs or who are con-
Whereas nonselective NSAIDs inhibit both sidered candidates for this therapy are at high car-
COX-1 and COX-2, selective COX-2 inhibitors act diovascular risk.25 Consequently, the studies lackedprimarily on COX-2.9 The selective COX-2 inhibi- adequate statistical power to confirm or refute a car-tors may therefore suppress vascular production diovascular hazard related to the use of COX-2 in-of prostacyclin without affecting the synthesis of hibitors.11 The use of active rather than placebo con-platelet-derived thromboxane A . This imbalance trols in many of these studies also made the findings
may promote thrombosis and increase the risk of difficult to interpret.cardiovascular events.10 Nonaspirin, nonselective
The results of the Vioxx Gastrointestinal Out-
NSAIDs may also not sufficiently reduce throm- comes Research (VIGOR) trial3 and a subsequentboxane A synthesis long enough to prevent plate- study, APPROVe,26 raised questions about the safety
let aggregation and atherosclerotic events.10 Other of rofecoxib. The VIGOR trial, which compared apotentially detrimental effects of COX-2 inhibi- nine-month course of 50 mg of rofecoxib per daytors have been suggested, including elevated blood (a larger dose than that usually recommended forpressure, though some reports have indicated that the long-term treatment of arthritis) with naproxenthese drugs may have beneficial effects on vascu- in patients with rheumatoid arthritis, reported alar health.23
higher risk of myocardial infarction among the pa-
In contrast to our findings, most of the earlier tients receiving rofecoxib.27 Some have attributed
clinical trials of selective COX-2 inhibitors in pa- these findings to the potentially cardioprotective ef-tients with arthritis did not appear to show an in- fects of naproxen,28,29 although this interpretationcrease in cardiovascular risk.2,5,14,24 These trials, has been a source of contention.18,20
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More recently, the APPROVe trial, a randomized,
placebo-controlled trial designed to evaluate the ef-
ficacy of rofecoxib for preventing colorectal polyps
in patients with a history of colorectal adenomas,
was terminated early because of an increased risk of
cardiovascular events.10,26 These results prompted
voluntary withdrawal of rofecoxib from the market.
Topol has reported that another controlled trial also
Estimated Probabilityof Composite End Point
showed an increased risk of cardiovascular events
with treatment with 12.5 mg of rofecoxib per day,
as compared with nabumetone or placebo.30
Months after First Dose
The results of other studies have aroused con-
No. at RiskCelecoxib, 400 mg
cern about the safety of selective COX-2 inhibitors.
In a placebo-controlled trial of pain relief after cor-
onary-artery bypass surgery, the use of the paren-teral COX-2 inhibitor parecoxib followed by oral
Figure 1. Kaplan–Meier Estimates of the Risk of the Composite End Point of
treatment with its active metabolite valdecoxib, or
Death from Cardiovascular Causes, Myocardial Infarction, Stroke, or Heart
treatment with placebo followed by valdecoxib, was
Failure among Patients Who Received Celecoxib (200 mg Twice Daily or 400 mg Twice Daily) or Placebo.
associated with a significantly increased risk of car-
The log-rank statistic of 8.73, which has two degrees of freedom, was used
diovascular thromboembolic events.31 In this issue
of the Journal, Nussmeier et al. report a second trialshowing a significant increase in cardiovascularevents when parecoxib and valdecoxib were used inthe immediate postoperative period after coronary- an increased cardiac risk associated with celecoxibartery bypass surgery.32 The Therapeutic Arthritis use in non–aspirin users, as compared with thoseResearch and Gastrointestinal Event Trial (TARGET) taking ibuprofen (but not diclofenac).20 Moreover,also showed a nonsignificant increase in the risk of the results of a randomized, controlled clinical trialcardiovascular events with lumiracoxib therapy,10 as of celecoxib in patients with Alzheimer’s disease,compared with naproxen or ibuprofen therapy, but reported to the Food and Drug Administration,only among patients who were not taking aspirin.
demonstrated an increase in cardiovascular events
In contrast, to our knowledge, neither phar- among patients receiving celecoxib.33
macoepidemiologic studies nor randomized, con-
Although we found that patients with an in-
trolled trials have reported clear evidence of an creased cardiovascular risk at baseline appeared toincreased cardiovascular risk associated with cele- have a higher absolute rate of events than those withcoxib. The failure of pharmacoepidemiologic stud- no increase in cardiovascular risk at baseline, for-ies to show an increased risk may be due in part to mal statistical tests of interaction showed no dif-the lower doses and shorter duration of use in these ferential effect of celecoxib with respect to baselinestudies than in clinical trials and in part to the po- cardiovascular risk. One prespecified subgroup in-tential for selection bias in nonrandomized studies. cluded users of cardioprotective aspirin at base-Nevertheless, the Celecoxib in Long-term Arthritis line. Although the overall absolute risk appeared toSafety Study (CLASS),2 which used the same dose be higher among such patients, analysis of the dataof celecoxib (400 mg twice daily) that was given to on aspirin users in this study shows that they had aone group in the APC study and compared celecoxib higher frequency of cardiovascular risk factors atwith two nonselective NSAIDs, did not show an in- baseline than did nonusers.creased rate of cardiovascular events.2 CLASS dif-
The cardiovascular findings with regard to cele-
fered from the VIGOR study in several important coxib use in the APC study are consistent with thoseways. A short-term study not designed for system- identified for rofecoxib use in the APPROVe trial. Inatic and formal assessment of cardiovascular contrast, preliminary analyses from the PreSAP trial,events, CLASS enrolled relatively low-risk patients which involved a daily dose of 400 mg of celecoxib,and allowed the use of aspirin for cardiovascular showed no apparent increase in cardiovascular risk.protection. In addition, FitzGerald has suggested The differences in the dosing regimens betweenthat CLASS did not completely refute evidence of these two trials — twice daily in the APC study, as
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The new england journal of medicine
Table 4. Incidence of Death from Cardiovascular Causes, Myocardial Infarction, Stroke, or Heart Failure According to Baseline Characteristics.Both Celecoxib Hazard Ratio P Value for SubgroupPatients(95% CI)*Interaction
compared with once daily in the PreSAP study — has substantial implications for public health,11,34support the hypothesis that sustained inhibition of patient education,35 and drug regulation.36,37 Givenprostacyclin may contribute to the increase in car- the experience with COX-2 inhibitors, we supportdiovascular risk. Other potential differences in the the call for regulatory agencies to consider request-trials, including geographic differences, differences ing a formal evaluation of long-term cardiovascu-in the patient population, and differences in use of lar outcomes of any new drug with a mechanism ofconcomitant medications, may have contributed to action that could augment the risk of cardiac andthe disparity in the preliminary findings.
vascular events, especially if many patients who are
The increased cardiovascular risk in the APC trial likely to use the new agent are prone to cardiovas-
was based on a small number of events in a trial that cular disease.25 This category may include nonse-was not designed or statistically powered to evalu- lective NSAIDs (other than aspirin), as discussedate cardiovascular risk. Although we believe we have earlier. More broadly, this experience underscoresidentified all adverse cardiovascular events, we can- both the need for long-term, placebo-controlled tri-not rule out the possibility that some events re- als to assess safety as well as efficacy and the needmained unreported. Our results must therefore be to improve methods for assessing potential adverseinterpreted with caution.
cardiovascular outcomes in studies with noncar-
Still, in the context of the results of the other tri- diovascular primary end points.
als reviewed involving agents in the same class,
In summary, a blinded review of cardiovascular
these data suggest that there may be a real increase events in a large, randomized, controlled study ofin cardiovascular risk associated with the use of cele- two doses of celecoxib for the prevention of colorec-coxib in particular and the class of selective COX-2 tal adenomas showed a dose-related risk of suchinhibitors in general. If correct, this interpretation events, including death from cardiovascular causes,
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myocardial infarction, stroke, and heart failure. In ib in preventing colorectal neoplasia and in reliev-light of other recent reports of the adverse cardio- ing pain.vascular effects of other agents in this class, these
The APC was sponsored by the National Cancer Institute and co-
data provide further evidence that long-term use of sponsored by Pfizer. This cardiovascular review was funded soley by
COX-2 inhibitors may increase the risk of serious
Drs. McMurray, Pfeffer, and Zauber report having received con-
cardiovascular events. These risks will need to be sulting fees from Pfizer. Drs. Solomon, McMurray, and Pfeffer re-weighed against any potential benefits of celecox- port having received lecture fees from Pfizer. Dr. Wittes reports hav-
ing received consulting fees from Merck within the past two years.
a p p e n d i x
The following persons participated in the APC Study: Steering Committee: M.M. Bertagnolli, E. Hawk, C. Eagle; Statistical Team: A. Zaub-er, K.M. Kim, D. Corle, R. Rosenstein, J. Tang, T. Hess, A. Wilton; Medical Monitors: W. Anderson, L. Doody; Central Pathology Review: M.Redston; Project Directors: M. Woloj, D. Bagheri, A. Crawford, M. Schietrum, V. Ladouceur; Data and Safety Monitoring Board: S. Rosen(chair), L. Friedman, R. Makuch, R. Phillips, P. Taylor; Principal Investigators: United States: S. Auerbach (California Professional Re-search, Newport Beach), C.F. Barish (Wake Research Associates, Raleigh, N.C.), T. Barringer (Carolinas Medical Center, Charlotte, N.C.),R.W. Bennetts (Northwest Gastroenterology Clinic, Portland, Oreg.), M. Blitstein (Associates in Gastroenterology and Liver Disease, LakeForest, Ill.), J. Bruggen (Wake Forest University Baptist Medical Center, Winston-Salem, N.C.), P. Carricaburu (Veterans Affairs Hospital,Sheridan, Wyo.), D. Chung (Massachusetts General Hospital, Boston), F. Colizzo (Pentucket Medical Associates, Haverhill, Mass.), R. Cur-tis (Newton–Wellesley Hospital, Newton, Mass.), T. Dewar (Harris Methodist Hospital Fort Worth, Ft. Worth, Tex.), R. DuBois (VanderbiltUniversity Medical Center, Nashville), T. Feinstat (Gastroenterology Consultants of Sacramento, Roseville, Calif.), T.R. Foley (RegionalGastroenterology Associates of Lancaster, Lancaster, Pa.), D. Gabbaizadeh (Huntington Research Group, Huntington Station, N.Y.), J.Geenen (Wisconsin Center for Advanced Research, Milwaukee), F. Giardiello (John Hopkins Hospital, Baltimore), A. Goetsch (nTouch Re-search, Huntsville, Ala.), M. Goldberg (Regional Gastroenterology Associates of Lancaster, Evanston, Ill.), J.L. Goldstein (University of Illi-nois at Chicago, Chicago), W. Harlan, III (Asheville Gastroenterology Associates, Asheville, N.C.), R. Hogan (Gastrointestinal Associates,Jackson, Miss.), M. Kamionkowski (Gastroenterology Associates of Cleveland, Mayfield Heights, Ohio), M. Kelfer (Fallon Clinic, WestBoylston, Mass.), B. Kerzner (Health Trends Research, Baltimore), K. Kim (University of Chicago Medical Center, Chicago), I. Klimberg(Gastroenterology Associates of Ocala, Ocala, Fla.), G. Koval (West Hills Gastroenterology Associates, Portland, Oreg.), C. Krone (Ad-vanced Clinical Therapeutics, Tucson, Ariz.), S. Krumholz (Waterside Clinical Research, West Palm Beach, Fla.), M.W. Layton (South PugetSound Clinical Research Center, Olympia, Wash.), C. Lightdale (Columbia-Presbyterian Medical Center, New York), P.J. Limburg (MayoClinic, Rochester, Minn.), C. Lind (Vanderbilt University Medical Center, Nashville), D. Lipkis (Institute for Health Care Assessment, SanDiego, Calif.), M. Lloyd (Idaho Gastroenterology, Meridian), D. Maccini (Spokane Digestive Disease Center, Spokane, Wash.), F. MacMilan,Sr. (Pentucket Medical Associates, Haverhill, Mass.), R. Madoff (University of Minnesota, Minneapolis), A. Malik (Advanced Clinical Re-search, North Providence, R.I.), A. Markowitz (Memorial Sloan-Kettering Cancer Center, New York), R. Marks (Alabama Digestive Re-search Center, Alabaster), C.J. McDougall (Manhattan Associates, New York), P. Miner (Oklahoma Foundation for Digestive Research,Oklahoma City), M. Murphy (Southeastern Digestive and Liver Disease Institute, Savannah, Ga.), A. Namias (Gastrointestinal Physicians,Salem, Mass.), N. Nickl (University of Kentucky Medical Center, Lexington), M. Pochapin (Jay Monahan Center for Gastrointestinal Health,New York), R.E. Pruitt (Nashville Medical Research Institute, Nashville), J. Puolos (Cumberland Research Associates, Fayetteville, N.C.),D.S. Riff (AGMG Clinical Research, Anaheim, Calif.), R. Roman (South Denver Gastroenterology, Englewood, Colo.), L. Rubin (New JerseyPhysicians, Passaic), D. Ruff (Healthcare Discoveries, San Antonio, Tex.), M. Safdi (Consultants for Clinical Research, Cincinnati), J. Saltz-man (Brigham and Women's Hospital, Boston), B. Salzberg (Atlanta Gastroenterology Associates, Atlanta), J.A. Sattler (Western ClinicalResearch, Torrance, Calif.), P. Schleinitz (Americas Doctors Research, Medford, Oreg.), J. Schwartz (Northwest Gastroenterologists, Ar-lington Heights, Ill.), M. Schwartz (Jupiter Research Association, Jupiter, Fla.), M. Silpa (Gastroenterology Associates of The East Bay Med-ical Group, Berkeley, Calif.), D. Silvers (Drug Research Services, Metairie, La.), D. Smoot (Howard University Cancer Center, Washington,D.C.), S. Sontag (Veterans Affairs Medical Center, Hines, Ill.), R.J. Sorrell (Gastroenterology Specialties, Lincoln, Nebr.), D. Stanton (Com-munity Clinical Trials, Orange, Calif.), J. Sturgeon (Americas Doctors Research, Shawnee Mission, Kans.), J.P. Tracey (Hawthorne MedicalAssociates, North Dartmouth, Mass.), T. Werth (Charlotte Gastroenterology and Hepatology, Charlotte, N.C.), C.M. Wilcox (University ofAlabama at Birmingham, Birmingham), R. Wohlman (Northwest Gastroenterology Associates, Bellevue, Wash.), S. Woods (Gastroenter-ology Associates of Fairfield County, Bridgeport, Conn.); United Kingdom: J. Burn (South Cleveland Hospital, Middlesbrough); Australia:E. Hoii (Sir Charles Gairdner Hospital, Nedlands, W.A.), M. Korman (Monash Medical Centre, Clayton, Victoria), A. Lee (Concord Repatri-ation and General Hospital, Concord, N.S.W.), B. Leggett (Royal Brisbane Hospital, Herston, Queensland), F. Macrae (Royal MelbourneHospital, Melbourne, Victoria), L. Mollison (Freemantle Hospital, Freemantle, W.A.), N. Yeomans (Western Hospital, Footscray, Victoria),G. Young (Flinders Medical Centre, Bedford, S.A.); Canada: G. Aumais (Hospital Maisonneuve-Rosemont, Montreal), R. Bailey (Hys Med-ical Centre, Edmonton, Alta.), C. Bernstein (Winnipeg Health Sciences Centre, Winnipeg, Man.), L. Cohen (Sunnybrook and Women'sHospital, Toronto), C. Dallaire, R. Dube (Centre Hospitalier Universitaire de Quebec, Quebec, Que.), D. Morgan (McMaster University,Hamilton, Ont.), T. Sylwestrowicz (St. Paul’s Hospital, Saskatoon, Sask.), G. Van Rosendaal (University of Calgary Health Sciences Centre,Calgary, Alta.), S.J. Van Zantan (Queen Elizabeth II Health Sciences Centre, Halifax, N.S.).r e f e r e n c e s
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Justice after transition: on the choices successor elites make in dealing with the past Coping with the past during the transition from repressive regime to democracy has taken a wide variety of forms.1 Strategies have ranged from massive criminal prosecution of the supporters of the previous order to unconditionally closing the book. All policy choices involve answers to two key questio

“Early stage projects always have a valuation. Possible reasons for the earlier negative NPV” statement, that all early-stage projects when discussing with people from pharmaceutical companies: “Early-stage • Over-conservative sales assumptions. never get to a positive value. Decisions are based on other criteria such as Let’s have a closer look at this: biotech posit